Multiple myeloma is a neoplastic disorder characterized by a clonal proliferation of malignant plasma cells, which produce monoclonal immunoglobulins (i.e., antibodies). Acute kidney injury (AKI) is a well-known complication of multiple myeloma with high tumor burden and high amounts of light chains (which are fragments of immunoglobulins) in the urine. AKI affects up to 50% of patients with multiple myeloma, and has important consequences: it exposes patients to the risk of permanent kidney damage (including end stage kidney failure), is associated with a decrease in overall survival, and impacts the treatment of the underlying myeloma.
In the vast majority of cases, AKI is due to myeloma cast nephropathy that results from the precipitation of complexes (called myeloma casts) formed by light chains and uromodulin (a protein normally present in urine) in the distal part of the nephron. See Leung et al., Adv Chronic Kidney Dis, 21: 36-47. These casts obstruct the nephrons, leading to AKI and induce an inflammatory reaction that leads to fibrosis and irreversible chronic kidney damage. The events leading to cast formation have been dissected. See Huang, et al., J Clin Invest, 92: 2975-83, 1993; Huang, et al., J Clin Invest, 99: 732-6, 1997. In particular, different light chains were found to bind to the same peptidic segment of uromodulin (later identified as D8C) and interacted with uromodulin through their CDJ3 (for complementarity-determining region 3). This finding led to the indentation of a CDJ3 sequence derived peptide that blocked the interaction between monoclonal light chains and uromodulin, and inhibited cast formation in vivo. See e.g., Ying, et al., Am J Pathol, 158: 1859-66, 2012.
Recognizing this result, peptides that inhibit the binding of light chains to uromodulin represent are an attractive targets for combating myeloma cast nephropathy and related conditions.